During development, progenitor cells produce a large diversity of young neurons that migrate away from their site of origin and establish distinct identities, including the formation of specific connections. The major aim of this research is to understand the cellular and molecular processes by which young neurons in the mammalian visual cortex achieve their adult identities during development, migrate to appropriate positions, and form axonal connections with appropriate target cells. Defects in the formation and elaboration of cortical circuits have fundamental implications for vision, cognition, and mental health, since defects in the migration and connectivity of cortical neurons are associated with a variety of disorders including epilepsy, dyslexia, schizophrenia, bipolar affective illness, and autism. The goals of our research are to identify the genes that regulate neurogenesis in the visual cortex and to understand how they affect the formation of cortical circuitry. We will explore the following specific issues: (1) Satb2 is a DNA-binding protein that regulates chromatin organization and is expressed in callosal projection neurons. To explore the role of Satb2 in fate determination, will analyze the axonal projections, electrophysiological properties, and gene expression patterns of neurons in mice with a conditional mutation of Satb2. (2) We will identify and characterize the downstream effectors of Satb2 and their roles in regulating the lamination and axonal projections of callosal projection neurons. (3) We found previously that the transcription factors Fezf2 and Ctip2 regulate the identity of subcortical projection neurons, and that Fezf2, Ctip2 and Satb2 interact genetically to form two mutually repressive pathways. We will explore how neurons decide between a subcortical vs. callosal projection neuron fate by exploring the genetic interactions between the Fezf2/Ctip2 and Satb2 pathways. (4) We will use transplantation methods to explore the acquisition of a subcortical vs. callosal projection neuron identity. By transplanting presumptive layer 6 cells into layer 2/3, and vice versa, we will ascertain whether and over what period of time a young cortical neuron can respond to local fate- inducing cues and alter its normal layer-specific identity, as assessed by its dendritic morphology, local and long distance axonal projections, and pattern of layer-specific gene expression.

Public Health Relevance

Defects in the formation and elaboration of cortical circuits have fundamental implications for vision, cognition, and mental health, since defects in the migration and connectivity of cortical neurons are associated with a variety of disorders including epilepsy, dyslexia, schizophrenia, bipolar affective illness, and autism. The goals of our research are to identify the genes that regulate neurogenesis in the visual cortex and to understand how they affect the formation of cortical circuitry.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY008411-22
Application #
8217221
Study Section
Central Visual Processing Study Section (CVP)
Program Officer
Steinmetz, Michael A
Project Start
2011-02-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
22
Fiscal Year
2012
Total Cost
$407,190
Indirect Cost
$157,190
Name
Stanford University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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Leone, Dino P; Srinivasan, Karpagam; Chen, Bin et al. (2008) The determination of projection neuron identity in the developing cerebral cortex. Curr Opin Neurobiol 18:28-35
Chen, Bin; Wang, Song S; Hattox, Alexis M et al. (2008) The Fezf2-Ctip2 genetic pathway regulates the fate choice of subcortical projection neurons in the developing cerebral cortex. Proc Natl Acad Sci U S A 105:11382-7
Alcamo, Elizabeth A; Chirivella, Laura; Dautzenberg, Marcel et al. (2008) Satb2 regulates callosal projection neuron identity in the developing cerebral cortex. Neuron 57:364-77
Chen, Bin; Schaevitz, Laura R; McConnell, Susan K (2005) Fezl regulates the differentiation and axon targeting of layer 5 subcortical projection neurons in cerebral cortex. Proc Natl Acad Sci U S A 102:17184-9
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Mackarehtschian, K; Lau, C K; Caras, I et al. (1999) Regional differences in the developing cerebral cortex revealed by ephrin-A5 expression. Cereb Cortex 9:601-10
Okada, A; Lansford, R; Weimann, J M et al. (1999) Imaging cells in the developing nervous system with retrovirus expressing modified green fluorescent protein. Exp Neurol 156:394-406

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